Summary of Work: The v-Ha-ras transgenic Tg.AC mouse behaves as a genetically initiated model for skin carcinogenesis (Leder, et al., 1990). Earlier work in our lab has demonstrated that the initiation of transgene expression is a critical event for skin tumorigenesis in this mouse (Hansen and Tennant, 1994a) and that papillomas may arise from susceptible populations of cells residing in the hair follicle (Hansen and Tennant, 1994b). The rapid response of the Tg.AC to some chemicals (including TPA and benzene) coupled with the low background of spontaneous skin tumors make this model a valuble tool for the study of other genes that may influence tumor development. To study the role of apoptosis in papilloma development, we crossed the Tg.AC mouse to the bcl-2+/- knockout mouse and subjected F1 progeny to TPA treatment. The initial experiment (Trempus, et. al., 1997) demonstrated that a low dose (1.25mg) of TPA, mice carrying the knockout allele developed fewer papillomas than wild type littermates, but at a higher dose of TPA (ie, 2.5 mg), this effect was not evident. Additional experiments are in progress using older mice (20 weeks at start of dosing). Preliminary results indicate that the knockout mice are developing fewer papillomas at both doses of TPA, with most profound difference occurring at the high dose of TPA, unlike the in the first experiment. We will also be using these mice to investigate the effect of farnesyl transferase inhibitors in TPA-promoted, bcl-2 deficient mice. Experiments involving progeny of Tg.AC crossed with COX-1 deficient mice to study the role of inflammation in tumor development are ongoing. To study the role of TGF-a in epidermal neoplasia, progeny of Tg.AC crossed with TGF-a knockouts were dosed with TPA. The data suggest that TGF-a does not play a strong role in tumor development in these mice, a respose likely influenced by the redundancy of the TGF-a gene family. Finally, we are currently developing protocols for the isolation of basal keratinocytes that express the transgene as a means to identify potential target cells for epidermal carcinogenesis. Also, studies are in progress in which suprabasal cells have been removed in order to more closely assess the role of the hair follicle in papilloma formation.